As noted above, in response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)) and, although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria in DSM-5. Since the inception of this project, approximately 200 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. Since irritable youth have decreased ability to tolerate frustration, this year we continued our work using frustrating tasks inside the fMRI scanner to define the neural circuitry mediating irritability. In a paper in press, we found that, when frustrated, youth with SMD had more difficulty than healthy subjects shifting their attention in order to meet task demands. In addition, when frustrated and receiving negative feedback, compared to healthy subjects, those with SMD exhibited decreased activation in the amygdala, striatum, and parietal regions. On the other hand, when subjects were frustrated and received positive feedback, there was no difference in brain activity between healthy subjects and those with SMD. These findings indicate that in response to negative feedback received in the context of frustration, youth with severe, chronic irritability show abnormally reduced activation in regions implicated in emotion, attention, and reward processing. We will now extend this work by adding comparison groups of youth with BD, anxiety, and attention deficit hyperactivity. In a hypothesis consistent with a Research Domain Criteria (RDoC) formulation, we posit that, across all of these groups, increased irritability will be associated with decreased attentional control and amygdala-parietal-striatal deactivation during frustration. In addition, in a collaboration with extramurally-funded investigators at Virginia Commonwealth University, we will be scanning monozygotic and dizygotic twins while they perform this frustrating task in order to quantify environmental and genetic contributions to the neural mechanisms mediating frustration in healthy youth. In this work, Importantly, our work conceptualizing irritability as a dimensional trait present in healthy youth and across different psychopathologies was greatly facilitated by our development of a brief but valid self- and parent-report instrument that could be used to measure irritability in youth. A variant of this scale was used in the field trials for DSM-5. Our scanning study in twins complements our published and ongoing work on the genetic epidemiology of irritability. In this work, we demonstrated that the heritability of irritability is approximately 0.4 (which is moderate for psychiatric illnesses or traits). Ongoing work is designed to describe the developmental trajectory of genetic influences on irritability i.e., the extent to which different genetic mechanisms mediating irritability come on-line as youth develop. Consistent with our finding on the frustration task, we also found attentional dyscontrol in irritable subjects on a task designed to ascertain abnormal attentional bias toward threatening faces. Thus, in both the frustration and the attentional bias tasks, we found attentional dyscontrol in irritable youth in negative emotional contexts. The abnormal attentional bias toward threat that we saw in irritable children is consistent with the bias seen in youth with anxiety, and adds to emerging data about mechanistic and clinical links between anxiety and irritability. This link has considerable public health importance, since anxiety is a frequent but often unrecognized cause of irritability in youth presenting for psychiatric care. Also, the mechanistic link that we discovered between irritability and anxiety is also consistent with our prior data showing that irritable youth are at increased risk to develop anxiety disorders as adults. Potentially, these associations between anxiety and irritability may also be relevant to treatment. Last year, we began a double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of SMD. Importantly, stimulant and SRI treatment tend to be less toxic than the atypical antipsychotic treatment that is considered first-line treatment for bipolar disorder, yet stimulants and SRI's are relatively contraindicated in patients with bipolar disorder because of concern about possibly inducing a manic episode. Therefore, this treatment trial has considerable public health importance. Thus far, we have randomized approximately 35 children into the trial, and youth are tolerating the experimental treatment well. In addition, we are assisting collaborators at UCLA on a similar trial that is funded extramurally. We are also now extending our treatment work to include an adjunctive trial of computer-based training designed to shift subject's perception of faces from angry toward happy. This work is based on our prior work demonstrating face emotion labeling deficits in youth with SMD, and work by our collaborators (Dr. Marcus Munafo at the University of Bristol and Dr. Yair Bar-Haim at Tel Aviv University) that such face labeling training can be associated with decreases in trait anger and irritability.